Rapid Access to Hydroxyfluoranthenes via a Domino Suzuki–Miyaura/Intramolecular Diels–Alder/Ring-Opening Reactions Sequence

In this work, we developed an efficient method for the rapid construction of fluoranthene skeleton to access a variety of substituted hydroxyfluoranthenes. The 1-iodo-8-alkynylnaphthalene derivatives, which serve as substrates for the key fluoranthene-forming step, were prepared via selective monoalkynylative Sonogashira reactions of 1,8-diiodonaphthalene. The domino reaction sequence which involves a sequential Suzuki–Miyaura coupling, an intramolecular Diels–Alder reaction, and an aromatization-driven ring-opening isomerization has been shown to give substituted hydroxyfluoranthenes in up to 92% yield. This work demonstrates the utility of designing new domino reactions for rapid access to substituted polycyclic aromatic hydrocarbons (PAHs).

P olycyclic aromatic hydrocarbons (PAHs) represent an important class of organic molecules that attracted significant attention from the synthetic community due to their diverse applications. 1 In particular, fluoranthenes constitute a widely encountered subclass of polycylic aromatic hydrocarbons, most members of which are fluorescent. 2 The optoelectronic properties of substituted fluoranthenes have culminated in a broad range of applications including design of fluorescent probes, 3 yellow and blue organic light emitting diodes (OLEDs, Figure 1, compounds 1 and 2), 4,5 thin film organic field-effect transistors (OFETs, compound 3), 6 and new materials for organic photovoltaic cells. 7 Moreover, benzo[j]fluoranthenes comprise the structural skeleton of many highly oxygenated, biologically active fungal natural products including truncatone C (4) 8 and daldinone B (5, Figure 1). 9,10 Catalytic methods using transition metal complexes, 11 Lewis acids, 12 or Brønsted acids 13 are among the most commonly applied transformations for the synthesis and derivatization of fluoranthenes. Cycloaddition and cyclization reactions have also been utilized for the construction of the fluoranthene skeleton from simpler building blocks. 3,4,14−16 For instance, inverse electron-demand Diels−Alder reactions of cyclopentadienone 6 with alkynes at high temperatures (200−220°C ) were shown to provide multisubstituted fluoranthenes (7) in an effective manner (Scheme 1a). 5,17 In a study reported by Lu, Wang and co-workers in 2011, the I 2 -mediated cyclization of dialkynylnaphthalenes (e.g., compound 8) resulted in the formation of iodofluoranthenes (Scheme 1b). 18 Compared to aryl-substituted fluoranthenes, direct access to hydroxyfluoranthenes has been rather underdeveloped. In a rare example of such a transformation, alkenyl ketone substrates 10 were reported to give complex hydroxyfluoranthenes 11 via an anionic-radical reaction cascade promoted by KHMDS (Scheme 1c). 19 Against this background, with the goal of discovering a direct method to access hydroxyfluoranthenes without the requirement of protection/deprotection steps, we designed the reaction sequence shown in Scheme 1d. According to this design, 1-iodo-8-alkynylnaphthalenes (12), which were planned to be prepared by a selective monoalkynylation of 1,8-diiodonaphthalene, would be sub-jected to a Suzuki−Miyaura coupling with 2-furylboronic acid under Pd catalysis. In the coupling products 13, furan and alkyne moieties are perfectly aligned in space for an intramolecular Diels−Alder reaction 20 to give cycloadducts 14, which were expected to undergo a ring opening reaction to release the ring strain and gain aromaticity to ultimately form hydroxyfluoranthenes 15. Moreover, we hypothesized that these three steps could proceed under the same reaction conditions resulting in a domino reaction sequence, 21 which would give directly the targeted hydroxyfluoranthene products. It is important to note that this hypothesis was based on the assumption that the reaction conditions for the initial Suzuki− Miyaura coupling would be suitable for the subsequent intramolecular Diels−Alder and ring-opening reactions.
In order to test our hypothesis, we first prepared alkynone 12a to be used in the designed domino reaction sequence (Scheme 2). For this purpose, 1,8-diiodonaphthalene (16) was subjected to a Sonogashira cross-coupling with propargylic alcohol 17a to afford the monoalkynylation product 18a in 71% yield. It should be noted that, in the Sonogashira reactions carried out in the present work, the use of an excess amount of 1,8-diiodonaphthalene (4 equiv) was found to be crucial to minimize the formation of dialkynylation products. Pleasingly, an unreacted excess of 1,8-diiodonaphthalene (16) was isolated with 75% recovery at the end of its Sonogashira reaction with alkyne 17a. Oxidation of alcohol 18a proceeded efficiently with MnO 2 giving the ketone product 12a in 91% yield. In the key domino reaction step, we were delighted to obtain hydroxyfluoranthene product 15a in an excellent yield of 92% upon the reaction of alkynone 12a with 2-furylboronic acid (19) in the presence of Pd(PPh 3 ) 4 (Scheme 2). We reckon that the initial Suzuki−Miyaura cross-coupling would form 13a, which would be both electronically and geometrically well-suited for an intramolecular Diels−Alder reaction to give pentacyclic intermediate 14a. Finally, the spontaneous aromatization-driven ring-opening isomerization of 14a would result in the formation of hydroxyfluoranthene 15a. This threestep sequence takes place under the same reaction conditions in a domino fashion obviating the need for the isolation of intermediates 13a and 14a.
With the validation of our hypothesis on the designed domino reaction sequence for fluoranthene synthesis, we next decided to investigate the scope of this methodology. To this end, we first synthesized 1-iodo-8-alkynylnaphthalene derivatives 12 which would serve as the precursors for the key domino reaction ( Table 1). The aryl-substituted alkynones 12b-g were prepared by an efficient two-step sequence. Initially, the highly selective monoalkynylative Sonogashira coupling reactions between 1,8-diiodonaphthalene (16) and propargylic alcohols 17 afforded monoiodoalkynol products in 70−85% isolated yields along with minimal formation of dialkynylation products (Table 1, entries 1−6). It is worth noting that this optimized protocol works successfully with both electron-rich and electron-deficient aryl groups as well as heteroaromatic substituents such as thiophene and furan. Among the methods tested for the oxidation of alkynols 18 to alkynones 12, PCC (pyridinium chlorochromate) 22 and Parikh-Doering oxidation 23 methods worked with moderate reaction yields. 24 On the other hand, both DMP (Dess-Martin periodinane) 25 and MnO 2 were found to be highly effective oxidants for this transformation with MnO 2 providing slightly higher yields. Overall, the oxidation of alkynols 18b-g to alkynones 12b-g were achieved in 53−90% yields (Table 1, entries 1−6). Finally, Me-substituted alkynone 12h and alkynyl amide 12i were synthesized in 53 and 82% yields, respectively, via the direct monoalkynylative Sonogashira coupling of 16 with the commercially available 3-butyn-2-one (20a) and propiolamide (20b) ( Table 1, entries 7 and 8). It is important to note that electron-deficient Me-substituted alkyne 20a was observed to undergo decomposition when Et 3 N was used both as base and the reaction solvent in the Sonogashira coupling, possibly via an aza-Michael-type reaction pathway. This decomposition was circumvented with the use of the bulkier and less nucleophilic Hunig's base (i-Pr 2 NEt) in the Sonogashira coupling along with DMSO as solvent. 26 With the alkynes 12b−i in hand, we next focused on their reactivity in the key domino reaction sequence for the synthesis of targeted hydroxyfluoranthenes. When alkynones 12b and 12c bearing electron-rich phenyl rings were reacted with 2-furylboronic acid (19) under the coupling conditions, hydroxyfluoranthenes 15b and 15c were isolated in 73% and 90% yields, respectively (Scheme 3). The domino reaction was observed to work successfully with electron-deficient aryl rings as well affording fluoranthene products 15d and 15e in good yields (69% and 52%, respectively). Afterward, we turned our attention to heteroaromatic alkynone substrates. We were pleased to see that the domino reaction of thienyl-substituted alkynone 12f gave the corresponding hydroxyfluoranthene 15f in excellent yield (91%). Gratifyingly, the furan ring present in 12g did not interfere in its reaction with 2-furylboronic acid (19), and the desired product 15g was isolated in 72% yield. The methyl-substituted alkynone 12h was also found to be a competent substrate in the domino sequence affording fluoranthene 15h, albeit in a lower yield (38%). Finally, the domino reaction sequence of the amide-containing substrate 12i led successfully to the formation of the desired product 15i in 53% isolated yield.
The phenolic −OH groups of the fluoranthene products 15a−i were all observed to make intramolecular hydrogen bonds with their neighboring ketone or amide carbonyls as revealed by the corresponding signals between 7.99 and 10.53 ppm in their 1 H NMR spectra. 27 In addition, the structure of amide-substituted fluoranthene product 15i was confirmed by single-crystal X-ray diffraction analysis (Figure 2a). The intramolecular hydrogen bond between the phenol −OH and the amide CO is clearly observed in this structure with an O−H···OC distance of 1.84 Å. Not surprisingly, the −CONH 2 group is tilted with a dihedral angle of 35.6°with respect to the plane of the phenol ring, possibly to minimize the steric repulsion between the naphthalene C−H and amide −NH 2 hydrogens. Interestingly, in addition to the intra- Yields refer to isolated product yields after purification by column chromatography. b In this reaction, Dess-Martin periodinane (DMP) was used as the oxidant. molecular hydrogen bond with the −OH group, the amide oxygen participates in two additional intermolecular hydrogen bonds with the −NH hydrogens of two adjacent fluoranthenes with N−H···OC distances of 2.10 and 2.21 Å (Figure 2b).
Finally, we sought to test the effectiveness of the intramolecular Diels−Alder reaction of alkynylnaphthalene substrates without electron-withdrawing groups. To this end, we first prepared aryl-substituted alkynes 12j and 12k to be used in the domino sequence (Scheme 4). The monoalkynylative Sonogashira coupling between 16 and phenylacetylene proceeded smoothly under the optimized conditions to afford iodoalkyne 12j in 84% yield. When 12j was subjected to the standard domino sequence conditions, Suzuki−Miyaura coupling product 13j was obtained as the major product in 92% yield (Scheme 4). This result is not surprising when the electron-rich nature of furan as a diene and the Ph-substituted alkyne as a dienophile in the structure of 13j is considered. However, when a pure sample of 13j was heated in mesitylene at 130°C, fluoranthene 15j was observed to form in 55% yield. This observation clearly supports the intermediacy of 1-furyl-8alkynylnaphthalenes en route to the formation of fluoranthenes in the developed domino reaction sequence. It should also be noted that the reaction between 12j and 19 with the use of Pd(PPh 3 ) 4 at 80°C in EtOH/water gave Suzuki−Miyaura product 13j in 53% yield along with the fluoranthene product 15j (14% yield) with a reaction time of 50 h. Next, in order to see the effect of an electron-withdrawing group on the aryl ring, 4-nitrophenyl-substituted iodoalkyne 12k was prepared in 86% yield via the Sonogashira reaction of 16 with 1-ethynyl-4nitrobenzene (21). The reaction of 12k with 2-furylboronic acid (19) gave hydroxyfluoranthene 15k in 25% yield, indicating a slight benefit of having an electron-withdrawing −NO 2 group on the aryl ring in the intramolecular Diels− Alder reaction with furan.
In summary, we have developed a new strategy to rapidly access substituted hydroxyfluoranthenes via a carefully designed domino reaction sequence. The first step of the newly developed method involves a selective monoalkynylative Sonogashira cross-coupling of 1,8-diiodonaphthalene that leads to the formation of a variety of 1-iodo-8-alkynylnaphthalenes. The propargylic alcohol derivatives 18a−g were oxidized to the corresponding ketones in high yields (53−91%). The key domino reaction sequence starting from iodoalkynes 12 and 2furylboronic acid with the use of Pd(PPh 3 ) 4 (5 mol %) afforded hydroxyfluoranthene products 15 effectively in up to 92% yield. This domino sequence consists of a Suzuki− Miyaura coupling, an intramolecular Diels−Alder reaction, and an aromatization-driven ring-opening isomerization, which all occur under the same reaction conditions. It is important to note that this method obviates the need to have protection/ deprotection steps on the −OH group, as it provides directly the hydroxyfluoranthene products at the end of the domino sequence. Studies to discover novel domino reactions to enable access to other types of polycyclic aromatic hydrocarbons are currently underway in our laboratory.
■ EXPERIMENTAL SECTION General Information. All reactions except the oxidation reactions of alcohols 18 with MnO 2 were performed using oven-dried glassware under an inert atmosphere of nitrogen. Aluminum-backed plates precoated with silica gel (Silicycle, 60 Å, F 254 ) were used for reaction monitoring by thin-layer chromatography (TLC). UV light (254 and 366 nm) and KMnO 4 staining solution were used for TLC Scheme 3. Scope of the Fluoranthene Synthesis visualization. Flash column chromatography was carried out using Silicycle 40−63 μm (200−400 mesh) flash silica gel. NMR spectra were recorded on a Bruker spectrometer at 400 MHz for 1 H NMR spectra and 100 MHz for 13 C{ 1 H} spectra, and calibrated from an internal standard (TMS, 0 ppm) or residual solvent signals (chloroform at 7.26 ppm for 1 H NMR spectra; chloroform at 77.16 ppm for 13 C NMR spectra). For 19 F{ 1 H}-NMR experiments, trifluoroacetic acid (CF 3 CO 2 H) was used as external reference (−76.55 ppm). 1 H NMR data are reported as follows: chemical shift (parts per million, ppm), integration, multiplicity (s = singlet, d = doublet, t = triplet, dd = doublet of doublets, m = multiplet, br = broad, app = apparent), coupling constant (Hz). Infrared (FTIR) spectra were recorded using a Bruker Alpha-Platinum-ATR spectrometer, and only selected peaks are reported. HRMS (high resolution mass spectrometry) analyses were performed on Agilent Technologies 6224 TOF LC/MS at the UNAM-National Nanotechnology Research Center and Institute of Materials Science and Nanotechnology, Bilkent University, and on Agilent Technologies 6530 QTOF-LC/MS at DAYTAM-East Anatolia High Technology Application and Research Center, Ataturk University. Single-crystal XRD analysis was performed at the Scientific and Technological Research Application and Research Center, Sinop University, Turkey. Melting points are uncorrected. Anhydrous CH 2 Cl 2 , THF, and 1,4dioxane were purchased from Acros Organics (AcroSeal). 1,8-Diaminonaphthalene was recrystallized from n-heptane prior to use. 2-Furylboronic (furan-2-boronic) acid was purchased from Acros Organics and used as received. Furan-2-boronic acid pinacol ester was prepared following a reported procedure. 28 Unless stated otherwise, all commercially available reagents were used without further purification.
General Procedure A for the Sonogashira Reaction Between Alkynes and 1, . To a solution of alkyne (1.0 equiv) and 1,8-diiodonaphthalene (16, 4 equiv) in Et 3 N or THF/Et 3 N, Pd(PPh 3 ) 2 Cl 2 (7 mol %) and CuI (14 mol %) were added at 23°C under N 2 . The resulting reaction mixture was stirred at 23°C until TLC showed full consumption of the alkyne. Usually, a color change from yellow to orange was observed. Et 3 N was removed under reduced pressure. The remaining residue was dissolved in a sufficient amount of EtOAc or CH 2 Cl 2 and washed once with H 2 O. The organic phase was dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography. Note: The use of 2 equiv of 1,8diiodonaphthalene was observed to afford the desired monoalkynylation product in considerably lower yield.